Involvement of cyclooxygenase-1, prostaglandin E2 and EP1 receptors in acid-induced HCO3- secretion in stomach

We investigated the cyclooxygenase (COX) isoforms as well as prostaglandin E receptor EP subtypes responsible for acid-induced gastric HCO3- secretion in rats and EP receptor-knockout (-/-) mice. Under urethane anesthesia, a chambered stomach (in the presence of omeprazole) was perfused with saline, and HCO3- secretion was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. Mucosal acidification was achieved by exposing the stomach for 10 min to 50 or 100 mM HCl Acidification of the mucosa increased the secretion of HCO3- in the stomach of both rats and WT mice, in an indomethacin-inhibitable manner. The acid-induced gastric HCO3- secretion was inhibited by prior administration of indomethacin and SC-560 but not rofecoxib in rats and mice. Acidification increased the PGE(2) content of the rat stomach, and this response was significantly attenuated by indomethacin and SC-560 but not rofecoxib, This response was also attenuated by ONO-8711 (EP1 antagonist) but not AE3-208 (EP4 antagonist) in rats and disappeared in EP1 (-/-) but not EP3 (-/-) mice. PGE2 increased gastric HCO3- secretion in both rats and WT mice, and this action was inhibited by ONO-8711 and disappeared in EP1 (-/-) but not EP3 (-/-) mice. These results support a mediator role for endogenous PGs in the gastric response induced by mucosal acidification and clearly indicate that the enzyme responsible for production of PGs in this process is COX-1. They further show that the presence of EP1 receptors is essential for the increase in the secretion of HCO3- in response to mucosal acidification in the stomach.